Synthesis of cannabinoids

ABSTRACT

The present invention relates to a process for the production of compound A comprising reacting compound B with compound C. A further ring closure reaction may be necessary. The invention further relates to certain novel compounds of formula B.

This application is a Division of U.S. application Ser. No. 10/479,021,filed Aug. 5, 2004, which is the U.S. National Phase application of PCTInternational Application No. PCT/GB02/02159, which claims priority ofGB 0112752.1.

The present invention relates to a novel process that can be used toproduce (−)-Δ⁹-tetrahydrocannibinol and related cannibinoid compounds.The invention further relates to novel compounds used in the process.

(−)-Δ⁹-Tetrahydrocannibinol (Δ⁹-THC) is the active ingredient inmarijuana. It is used therapeutically as an inhalant or an oral drug forstimulation of appetite among AIDS and cancer chemotherapy patients.Related cannibinoid compounds that show pharmacological activity arealso known. In particular, there have been attempts to produce watersoluble analogues of Δ⁹-THC (‘The Total Synthesis of Cannibinoids’ inThe Total Synthesis of Natural Products, Vol 4, John ApSimon, Wiley,1981, pp 239-243).

The chemical synthesis and isolation of Δ⁹-THC are both challenging.Δ⁹-THC is a very high boiling, viscous liquid. It is very prone toacid-catalysed isomerization to the thermodynamically more stable Δ⁸isomer, it is easily oxidized by oxygen to inactive cannibinol, and itis sensitive to light and heat. All of these factors make purificationdifficult, especially on an industrial scale, and chromatography hasgenerally been used.

Previous syntheses of Δ⁹-THC have tended to be either lengthy orlow-yielding. Most involve coupling of a chiral terpene to a resorcinolderivative. The primary difficulty has been lack of selectivity in thecoupling. Acid catalysed couplings have generally led to mixtures ofproducts (Crombie et al, J Chem Soc. Perkin Trans. I 1988 1243).Attempts to avoid the selectivity problem by using base-catalysedcoupling reactions have involved lengthier syntheses overall (Rickardset al, J. Org. Chem. 1984 49 572). Syntheses not using chiral terpeneshave yielded racemic product (Childers et al, J. Org. Chem. 1984 495276).

In seemingly the best known method (U.S. Pat. No. 5,227,537), Stossclaims that acid-catalysed coupling of (+)-p-menth-2-ene-1,8-diol (1)with olivetol (2) can be stopped at the intermediate Friedel-Craftsproduct (3), and then the intermediate (3) can be isolated and convertedin good yield to Δ⁹-THC using ZnBr₂ (24 hours, refluxing CH₂Cl₂). Thepresent inventors have encountered several problems with this scheme.The initial p-toluenesulfonic acid catalysed Friedel-Crafts reaction wasdifficult to stop cleanly at the intermediate (3) under Stoss'conditions and gave mixtures of the intermediate (3) and Δ⁹-THC, thering-closed product. Any Δ⁹-THC formed is likely to isomerize to Δ⁸-THCunder the disclosed conditions. The use of a heavy metal such as ZnBr₂in the last step of an industrial process is highly undesirable as itmay lead to traces of metal in the product, and this is especiallyundesirable for pharmaceuticals. Stoss' method therefore appears tooffer no real advantage in yield or purity of Δ⁹-THC over a one-potcoupling that goes directly to Δ⁹-THC. Razdan has published a one-potmethod for coupling of (+)-p-menth-2-ene-1,8-diol (1) with olivetol (2)to produce Δ⁹-THC (Razdan et al, Tet. Lett. 1983 24 3129). This alsosuffers from several problems: it uses nearly 14 equivalents of ZnCl₂ asthe acid, and uses six equivalents of olivetol (2). Even under theseconditions, the yield is still only 28% from (+)-p-menth-2-ene-1,8-diol(1).

Thus there is a need for a short, practical, high-yielding synthesis ofΔ⁹-THC that can be practised on an industrial scale. This is the problemthat the present inventors have set out to address.

DETAILED DESCRIPTION OF THE INVENTION

The entire disclosure of U.S. patent application Ser. No. 10/479,021,filed Aug. 5, 2004, is expressly incorporated by reference herein.

Accordingly the present invention provides a process for the productionof a compound of general formula A:

wherein R^(c), R^(d) and R^(e) are independently H, alkyl, orsubstituted alkyl; and R¹ to R⁴ are independently H, OH, OR′ (R′ isalkyl, aryl, substituted alkyl or aryl, silyl, acyl, or phosphonate),alkyl, substituted alkyl, aryl, acyl, halide, amine, nitrate, sulphonateor phosphonate;comprising reacting compound B with compound C:

wherein R^(a) is H, alkyl, aryl, acyl or silyl; R^(b) is alkyl, aryl oracyl; R^(c), R^(d), R^(e) and R¹ to R⁴ are as hereinbefore defined;and comprising, when necessary, a ring closure reaction.Preferably the reaction of compound B with compound C is carried out inthe presence of an acid catalyst.

A substituted alkyl group may contain substituents such as halide,hydroxyl, amine and thiol. Alkyl groups may be saturated or unsaturated,acyclic or cyclic.

Compound B is similar to the (+)-p-menth-2-ene-1,8-diol used in theStoss method. However, compound B is not a diol, and contains one ormore ether or ester groups. R^(b) is alkyl, aryl or acyl, and preferablyR^(a) is independently alkyl, aryl or acyl.

In a preferred embodiment, R^(b) is acyl, and OR^(b) is an ester group.Suitable ester groups include acetate, propionate, butyrate,trimethylacetate, phenylacetate, phenoxyacetate, diphenylacetate,benzoate, p-nitrobenzoate, phthalate and succinate.

In an especially preferred embodiment both R^(a) and R^(b) are acylgroups so that compound B is a diester. The two ester groups aresuitably chosen independently from acetate, propionate, butyrate,trimethylacetate, phenylacetate, phenoxyacetate, diphenylacetate,benzoate, p-nitrobenzoate, phthalate and succinate. An especiallypreferred compound has OR^(a)=OR^(b)=diphenylacetate:

R^(c), R^(d) and R^(e) can be varied independently of R^(a) and R^(b)and will affect the structure of the product, compound A. R^(c) issuitably Me or H, preferably Me. R^(d) and R^(e) are suitably Me orCH₂OH, preferably Me.

Compound C is a phenolic compound and is preferably a resorcinolderivative such as olivetol (3).

R¹ is preferably OR″ wherein R″ is H, alkyl, substituted alkyl, acyl orsilyl. Most preferably R¹ is OH.

Preferably, R² and R⁴ are H.

R³ is suitably an alkyl group or substituted alkyl group. In a preferredembodiment, R³ is C₅H₁₁. R³ may contain groups that promote watersolubility, e.g. ketone, ester, hydroxyl or amine groups. In oneembodiment of the invention, R³ contains a thioketal (this can befurther converted to an aldehyde).

Most preferably, compound C is olivetol (3), wherein R¹ is OH, R² is H,R³ is C₅H₁₁ and R⁴ is H.

Suitably, one equivalent of compound B is reacted with approximately oneequivalent of compound C.

In a preferred embodiment of the invention compound B is an ether orester of (+)-p-menth-2-ene-1,8-diol (R^(c)=Me, R^(d)=Me, R^(e)=Me),compound C is olivetol (R¹=OH, R²=H, R³=C₅H₁₁, R⁴=H) and the product,compound A, is Δ⁹-THC.

The present invention therefore provides a novel synthesis of Δ⁹-THC.

The present invention provides both a one-step and a two-step processfor the production of compound A. In the one-step process the reactionof compound B and compound C produces compound A directly. In theone-step process, suitably about one equivalent of acid catalyst isused, e.g. between 0.8 to 1.5 equivalents. Preferably the reaction iscarried out below 0° C., most preferably from −20° C. to 0° C.

In the two-step process the reaction of compound B and compound Cproduces a ring-opened product, compound D:

For the two-step process, suitably less than one equivalent of acid isused, preferably from 0.1 to 0.5 equivalents. Preferably the reaction iscarried out below 0° C., more preferably below −10° C. A ring closurestep is then carried out. Suitable reagents for the ring closure stepinclude acids such as BF₃.(OEt)₂ or TsOH. One possible advantage of thetwo-step process is that if compound D is a crystalline solid,purification of the intermediate is straightforward and this may lead tohigher purity in the final product, compound A.

The present invention provides one-step and two-step syntheses that canbe used to produce Δ⁹-THC. The syntheses show improved selectivity andyield compared to prior art methods. The amount of isomers generated issmall and purification is simple. The phenolic reactant (compound C) isnot used in excess. The process is suitable for scale-up to anindustrial process.

Preferably the yield of the synthesis of Δ⁹-THC is greater than 50%,more preferably the yield is greater than 75%. The process also provideshigh purity Δ⁹-THC. Preferably Δ⁹-THC is obtained in greater than 70%purity, more preferably greater than 90% purity. Methods known in theart can be used to further purify the products of the reaction.

The process of the present invention is suitably carried out in a polaraprotic solvent, preferably methylene chloride.

Suitable acid catalysts include most Lewis acids. Non-metallic catalystssuch as BF₃.OEt₂ and toluenesulfonic acid are preferred. Non-metalliccatalysts offer advantages over the zinc catalysts used in the Stoss andRazdan methods because there is no possibility of a metal residue in theproduct. BF₃.OEt₂ is preferred because it is easily removed from thereaction mixture, and is less prone to causing isomerisation of Δ⁹-THCto Δ⁸-THC than p-TsOH. Suitably about one equivalent of catalyst or lessis used, e.g. 0.1 to 1.5 equivalents. This offers a clear improvementover Razdan's method where 14 equivalents of acid are used.

Procedures for isolating the product, compound A, from the reactionmixture are well known to those in the art. Chromatography can be usedto purify the product.

Certain compounds of structure B are novel and are particularlyadvantageous when used in the present invention. Compounds wherein bothOR^(a) and OR^(b) are chosen independently from acetate, propionate,butyrate, trimethylacetate, phenylacetate, phenoxyacetate,diphenylacetate, benzoate, p-nitrobenzoate, phthalate and succinate(provided that only one of OR^(a) and OR^(b) is acetate) represent afurther aspect of this invention. Preferably the groups are chosen sothat compound B is a solid. Preferably both OR^(a) and OR^(b) arediphenylacetate. Preferably, R^(c), R^(d) and R^(e) are Me.

Compound B can be produced by a variety of methods. Compounds whereinR^(a)=H or silyl can be prepared by the ring-opening of epoxides (5)with an alcohol, a carboxylic acid or silylated derivatives of alcoholsand carboxylic acids. Reactions of this type are described in aco-pending patent application by the present inventors.

Compounds wherein R^(a) and R^(b) are both the same can be produced bybase catalysed reaction of the corresponding diol (6) with anhydrides orchlorides.

Compounds wherein R^(a) is not H or silyl and wherein R^(a) and R^(b)are different can be produced by base-catalysed reaction of mono-ethersor mono-esters (7) with ethers or chlorides.

The following examples are illustrative but not limiting of theinvention.

GENERAL EXPERIMENTAL DETAILS

Anhydrous solvents were purchased from Aldrich Chemical Company(Milwaukee, Wis., USA). Samples of Δ⁹-THC and Δ⁸-THC were obtained fromRBI/Sigma (Natick, Mass., USA). (+)-p-Menth-2-ene-1,8-diol was preparedas described in a co-pending patent application by the presentinventors. TLC plates (silica gel GF, 250 micron, 10×20 cm) werepurchased from Analtech (Newark, Del., USA). TLCs were visualized undershort wave UV, and then by spraying with ceric ammonium nitrate/sulfuricacid and heating. Column chromatography was carried out using TLC gradesilica gel purchased from Aldrich Chemical Company. NMR spectra wereobtained on a Bruker 300 MHz instrument. HPLC area percentages reportedhere are not corrected. HPLCs were run on Shimadzu LC-10AD.

EXAMPLE 1a One-step Reaction of Bis(diphenylacetate) Compound (4) withOlivetol (3) to Produce Δ⁹-THC Preparation of Bis(diphenylacetate)Compound (4)

A 25 ml three-necked roundbottom flask with a stir bar was oven-dried,fitted with septa, and cooled under N₂. Pyridine (12 ml) was added andthe pale yellow solution was stirred. Diphenylacetyl chloride (5.69 g,4.2 eq.) was added. The solution turned brown. N,N-dimethylaminopyridine(0.1435 g, 0.2 eq.) was added. The mixture was stirred for 1 hour.(+)-p-Menth-2-ene-1,8-diol (1.00 g) was added. The mixture became alighter colour and solids precipitated. The slurry was allowed to stirovernight at room temperature. The reaction was quenched with water. Themixture was extracted three times with ethyl acetate. The organics werecombined and washed with 2M HCl, saturated NaHCO₃, and saturated NaCl(aq.), dried over Na₂SO₄, filtered and concentrated in vacuo to orangeoil. The oil was dissolved in hot methanol and cooled to crystallize.The white solid was collected and washed twice with cold methanol. Afterdrying under vacuum, the yield was 3.282 g (76.8% yield). ¹H NMR(CDCl₃): δ (ppm) 7.4-7.2 (m, 20H), 5.89-5.84 (dd, 1H), 5.51-5.47 (dd,1H), 4.90 (s, 2H), 2.7-2.6 (m, 1H), 2.0-1.9 (m, 2H), 1.7-1.6 (m, 1H),1.43 (s, 3H), 1.42 (s, 3H), 1.40 (s, 3H), 1.35-1.2 (m, 1H). ¹³C NMR: δ(ppm) 171.47, 171.44, 139.06, 138.84, 132.38, 128.64, 128.56, 128.51,128.46, 128.28, 127.11, 127.07, 127.02, 85.12, 80.91, 58.32, 57.86,44.22, 33.81, 25.41, 23.32, 22.81, 21.41. M.p. 111° C. ElementalAnalysis: 81.66% C, 6.59% H. R_(f) (20% EtOAc/hexane): 0.54. [α]_(D)²⁵=+61.5° (c=1.00, CHCl₃). IR (KBr, cm⁻¹): 3061, 3028, 1720.5 (carbonylstretch).

One-step Reaction

A 25 ml roundbottom flask with a stir bar was oven-dried, fitted withsepta, and cooled under N₂. The bis(diphenylacetate) (4) (279 mg, 0.499mmol) and olivetol (90 mg) were added. Anhydrous CH₂Cl₂ (8 ml) was addedand stirred. The solution was cooled to −5° C. internal temperature.BF₃.(OEt)₂ (64 μl, 1.0 eq.) was added. The solution gradually darkenedto orange. After 30 minutes, the reaction was quenched with 10% Na₂CO₃(10 ml). The layers were separated and the organic layer was washed with2×5 ml 10% Na₂CO₃. The aqueous washes were combined and extracted twicewith CH₂Cl₂. The organics were combined and washed with water andsaturated NaCl solution, then dried over Na₂SO₄, filtered, andconcentrated in vacuo to light yellow oil. The oil was chromatographedon 5 g TLC mesh silica to yield 135.2 mg (86.1%) of Δ⁹-THC. NMR did showa small amount of solvent present. HPLC showed 96.6 area percent Δ⁹-THC.¹H NMR agreed with published reports and commercial samples. ¹³C NMR(CDCl₃): δ (ppm) 154.81, 154.16, 142.82, 134.41, 123.74, 110.11, 107.54,77.18, 45.83, 35.47, 33.58, 31.52, 31.17, 30.63, 27.58, 25.03, 23.34,22.53, 19.28, 13.99. HPLC R.T.: 28.34 min. R_(f) (10% MTBE/hexane):0.30. [α]_(D) ²⁵=−174.2° (c=1.16, EtOH).

EXAMPLE 1b Reaction of Bis(diphenylacetate) (4) Compound with Olivetolto Produce Ring-open Intermediate

Bis(diphenylacetate) (4) was prepared as for example 1a.

A 25 ml 2-neck roundbottom flask with a stir bar was oven-dried, fittedwith septa, and cooled under N₂. Bis(diphenylacetate) (4) (279 mg, 0.499mmol) and olivetol (90 mg) were added. Anhydrous CH₂Cl₂ (8 ml) wasadded. The solution was stirred to dissolve the solids and then cooledto −20° C. internal temperature. BF₃.(OEt)₂ (16 μl, 0.25 eq.) was added.The solution was stirred for 12 minutes and then quenched with 10%Na₂CO₃ (aq.) (6 ml). The mixture was extracted twice with CH₂Cl₂. Thecombined organics were washed with water and saturated NaCl, dried overNa₂SO₄, filtered, and concentrated in vacuo to oil. Chromatography on 10g TLC mesh silica gel (2% MTBE/hexane-15%) yielded Δ⁹-THC (fractions16-22, 31.4 mg, 20.0% yield), but the predominant product was thediphenylacetate triol (the ring open product corresponding to compoundD) (fr. 24-37, 160 mg, 60.7% yield). ¹H NMR (CDCl₃): δ (ppm) 7.26-71.8(m, 10H), 6.26 (br s, 1H), 6.04 (br s, 1H), 5.35 (s, 1H), 4.51 (s, 1H),3.92 (br d, 1H), 2.43-2.36 (m, 3H), 2.1-1.9 (m, 2H), 1.79 (m, 1H), 1.71(s, 3H), 1.6-1.4 (m, 2H), 1.44 (s, 3H), 1.42 (s, 3H), 1.3-1.2 (m, 4H),0.85 (t, 3H). ¹³C NMR (CDCl₃) δ ppm 171.56, 142.87, 139.24, 139.08,128.64, 128.36, 128.31, 126.92, 126.89, 124.93, 115.43, 87.27, 57.53,45.94, 35.43, 33.46, 31.51, 30.60, 29.96, 24.04, 23.34, 23.20, 23.17,22.48, 13.97. R_(f) (20% EtOAc/hexane): 0.48. [α]_(D) ²⁵=−45.9°(c=1.298, CHCl₃). Elemental Analysis: 78.69% C, 8.93% H.

EXAMPLE 2a One-step Reaction of Monoacetate Compound (8) with Olivetolto Produce Δ⁹THC

A 25 ml roundbottom flask with a stir bar was oven-dried, fitted withsepta, and cooled under N₂. The monoacetate (8) (109 mg) and olivetol(92.5 mg) were added. Anhydrous CH₂Cl₂ (8 ml) was added and stirred. Thesolution was cooled to −5° C. internal temperature. BF₃.(OEt)₂ (65 μl,1.0 eq.) was added. The solution gradually darkened to orange. After 24minutes, the reaction was quenched with 10% Na₂CO₃. The layers wereseparated and the aqueous layer was extracted twice with CH₂Cl₂. Theorganics were combined and washed with water and saturated NaClsolution, then dried over Na₂SO₄, filtered, and concentrated in vacuo tooil. HPLC showed 64.0 area percent Δ⁹-THC. The oil was chromatographedon 20 g TLC mesh silica to yield 58.7 mg (36.3%) of Δ⁹-THC. ¹H NMRagreed with published reports and commercial samples.

EXAMPLE 2b Reaction of Monoacetate Compound (8) with Olivetol to ProduceRing-open Intermediate

A 25 ml 2-neck roundbottom flask with a stir bar was oven-dried, fittedwith septa, and cooled under N₂. The monoacetate (8) (109 mg, 0.514mmol) and olivetol (92.5 mg) were added. Anhydrous CH₂Cl₂ (8 ml) wasadded. The solution was stirred to dissolve the solids and then cooledto −20° C. internal temperature. BF₃.(OEt)₂ (16 μl, 0.25 eq.) was added.The solution was stirred for 45 minutes and then quenched with 10%Na₂CO₃ (aq.) (4 ml). The mixture was extracted twice with CH₂Cl₂. Thecombined organics were washed with water, dried over Na₂SO₄, filtered,and concentrated in vacuo to a colourless oil. Chromatography on silicagel yielded 90.5 mg (47.0% yield) of acetyl triol (the ring open productcorresponding to compound D). ¹H NMR (CDCl₃): δ (ppm) 6.22 (br m, 2H,),5.76 (br s, 2H), 5.36 (s, 1H), 4.00 (br d, 1H), 2.67 (dt, 1H), 2.40 (t,2H), 2.26-2.16 (br m, 2H,), 2.07-1.90 (m, 2H), 1.73 (s, 3H), 1.51 (s,3H), 1.49 (s, 3H), 1.42 (s, 3H), 1.32-1.24 (m, 4H), 0.85 (t, 3H). ¹³CNMR (CDCl₃): δ (ppm) 170.83, 142.69, 138.03, 124.99, 115.42, 85.90,44.29, 35.38, 33.47, 31.49, 30.66, 30.09, 25.16, 24.65, 23.17, 22.57,22.43, 21.84, 13.95. R_(f) (20% EtOAc/hexane): 0.37.

EXAMPLE 3a One-step Reaction of Monomethoxy Compound (9) with Olivetolto Produce Δ⁹-THC

A 25 ml roundbottom flask with a stir bar was oven-dried, fitted withsepta, and

cooled under N₂. The monomethoxy compound (9) (91.9 mg) and olivetol (90mg) were added. Anhydrous CH₂Cl₂ (8 ml) was added and stirred. Thesolution was cooled to −5° C. internal temperature. BF₃.(OEt)₂ (16 μl,0.25 eq.) was added. After 1 hour another 16 μl was added. Two hourslater, another 32 μl was added. The solution gradually darkened toorange. TLC showed a mixture of Δ⁹-THC and the ring open product, andtwo other major spots. The reaction was quenched with 10% Na₂CO₃. Thelayers were separated and the organic was washed with water and sat.NaCl, then dried over Na₂SO₄, filtered, and concentrated in vacuo tooil.

EXAMPLE 3b Reaction of Monomethoxy Compound with Olivetol to ProduceRing-open Intermediate

A 5 ml roundbottom flask with a stir bar was oven-dried, fitted with aseptum, and cooled under N₂. The monomethoxy compound (9) (33.5 mg) in1.5 ml of anhydrous methylene chloride was added. Olivetol (32.7 mg) andmagnesium sulfate (134 mg) were added. p-Toluenesulfonic acidmonohydrate (34.6 mg) was added. The slurry was stirred at roomtemperature for 30 minutes. Solid NaHCO₃ (100 mg) was added and stirred.The solids were removed by filtration. The solution was washed once with5% NaHCO₃ (aq.). The aqueous wash was extracted once with CH₂Cl₂. Theorganics were combined, washed with water, and dried over Na₂SO₄. Thesolution was concentrated in vacuo and chromatographed on silica gel.Colourless oil of the methoxy triol (the ring open product correspondingto compound D) (35.3 mg, 56.0% yield) was obtained. ¹H NMR (CDCl₃): δ(ppm) 7.90 (br s, 1H), 6.68 (br s, 1H), 6.33-6.21 (br d, 2H) 5.75 (s,1H), 3.74 (s, 1H), 3.20 (s, 3H), 2.44 (t, 2H), 2.07 (br s, 2H),2.00-1.77 (m, 3H), 1.80 (s, 3H), 1.54 (m, 2H), 1.31 (m, 3H), 1.14 (s,3H, 1.13 (s, 3H), 0.87 (t, 3H). ¹³C NMR (CDCl₃): δ (ppm) 186.50, 169.63,166.85,143,41, 140.11, 123.58, 79.32, 48.63, 48.05, 35.51, 32.62, 31.52,30.63, 27.76, 23.74, 23.01, 22.53, 21.95, 20.39, 13.99. ElementalAnalysis: 73.3% C, 8.80% H. R_(f) (10% EtOAc/hexane): 0.25. [α]_(D)²⁵=−22.7° (c=0.088, CHCl₃).

EXAMPLE 4 One-step Reaction of Diacetate (10) with Olivetol to ProduceΔ⁹-THC Preparation of Diacetate (10)

A 100 ml three-necked roundbottom flask with a stir bar was oven-dried,fitted with septa, and cooled under N₂. (+)-p-menth-2-ene-1,8-diol(10.00 g) was added. Triethylamine (68.7 ml, 8.4 eq.) was added and theslurry was stirred. N,N-dimethylaminopyridine (1.435 g, 0.2 eq.) wasadded. Acetic anhydride (23.3 ml) was placed in an addition funnel andadded slowly over 15 minutes. The yellow solution became homogeneous.The solution was warmed to 35° C. internal temperature and stirred for2.5 ours, then raised to 40° C. for another three hours, then allowed tostir for 13 hours at room temperature. The reaction was quenched withwater while cooling in ice. The mixture was extracted three times withhexane and once with ethyl acetate. The organics were combined andwashed with saturated NaCl (aq.), dried over Na₂SO₄, filtered andconcentrated in vacuo to an orange oil. Chromatography on 50 g TLC meshsilica yielded the diacetate (10) as a colourless oil (12.3 g, 82.3%).The oil was cooled in dry ice to freeze the oil and then the solid wasbroken up with a spatula. It was allowed to warm to room temperature andit remained a white solid. ¹H NMR (CDCl₃): δ (ppm): 5.84 (dd, 1H), 5.54(dd, 1H), 2.70 (m, 1H), 2.05-1.8 (m, 3H), 1.85 (s, 6H), 1.68 (m, 1H),1.40 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H). ¹³C NMR (CDCl₃): δ (ppm)169.95, 169.89, 132.40, 127.88, 83.79, 79.73, 43.62, 33.85, 25.26,23.10, 22.74, 22.05, 21.49. m.p. 28-31° C. Elemental Analysis: 65.26% C,8.61% H. R_(f) (20% EtOAc/hexane): 0.52. [α]_(D) ²⁵=+73.5° (c=0.99,CHCl₃).

One-step Reaction

A 25 ml roundbottom flask with a stir bar was oven-dried, fitted withsepta, and cooled under N₂. The diacetate (10) (126.9 mg, 0.499 mmol)and olivetol (90 mg, 0.499 mmol) were added. Anhydrous CH₂Cl₂ (8 ml) wasadded and stirred. The solution was cooled to −5° C. internaltemperature. BF₃.(OEt)₂ (64 μl, 1.0 eq.) was added. The solutiongradually darkened to red. After 15 minutes, the reaction was quenchedwith 10% Na₂CO₃. The layers were separated and the organic layer waswashed with 10% Na₂CO₃. The combined aqueous were extracted once withCH₂Cl₂. The organics were combined and washed with water and saturatedNaCl solution, then dried over Na₂SO₄, filtered, and concentrated invacuo to a tannish oil (0.132 mg). HPLC showed 88.8 area percent Δ⁹-THC.Chromatography on silica gel yielded 95.9mg (61.0% yield) of Δ⁹-THC.HPLC showed 94.9 area percent Δ⁹-THC.

EXAMPLE 5 One-step Reaction of Dibenzoate (11) with Olivetol to ProduceΔ⁹-THC Preparation of Dibenzoate (11)

A 25 ml three-necked roundbottom flask with a stir bar was oven-dried,fitted with septa, and cooled under N₂. (+)-p-Menth-2-ene-1,8-diol (1.00g) was added. Pyridine (6 ml, 12.6 eq.) was added and the pale yellowsolution was stirred. N,N-dimethylaminopyridine (0.1435 g, 0.2 eq.) wasadded. Benzoyl chloride (2.73 ml, 4 eq.) was added. After 10 minutes, asolid precipitated. The slurry was allowed to stir overnight at roomtemperature. The reaction was quenched with water. The mixture wasextracted three times with CH₂Cl₂. The organics were combined and washedwith water and saturated NaCl (aq.), dried over Na₂SO₄, filtered andconcentrated in vacuo. The oil was chromatographed on 25 g TLC meshsilica to yield a colourless oil. The oil was cooled in dry ice andfroze, but melted on warming to room temperature. ¹H NMR(CDCl₃) δ (ppm):8.0 (dt, 4H), 7.51 (m, 2H), 7.40 (dt, 4H), 6.16 (dd, 1H), 5.88 (dd, 1H),3.00 (m, 1H), 2.29 (m, 2H), 2.02 (m, 1H), 1.70 (s, 3H), 1.62 (s, 3H),1.60 (s, 3H), 1.25 (m, 1H). ¹³C NMR (CDCl₃) δ (ppm): 165.53, 132. 80,132.53, 132.50, 131.77, 131.63, 129.40, 129.36, 128.39, 128.22, 128.16,80.64, 44.55, 34.09, 25.81, 23.50, 23.10, 22.59, 21.99, 14.14, 14.05.Elemental Analysis: 76.21% C, 6.97% H. R_(f) (20% EtOAc/hexane): 0.57.

One-step Reaction

A 25 ml roundbottom flask with a stir bar was oven-dried, fitted withsepta, and cooled under N₂. The dibenzoate (11) (189 mg, 0.499 mmol) andolivetol (90 mg) were added. Anhydrous CH₂Cl₂ (8 ml) was added andstirred. The solution was cooled to −5° C. internal temperature.BF₃.(OEt)₂ (64 μl, 1.0 eq.) was added. The solution gradually darkenedto red. After 15 minutes, the reaction was quenched with 10% Na₂CO₃. Thelayers were separated and the organic layer was washed with water andsaturated NaCl solution, then dried over Na₂SO₄, filtered, andconcentrated in vacuo to oil. HPLC showed 78.8 area percent Δ⁹-THC.

EXAMPLE 6 One-step Reaction of Di-p-nitrobenzoate (12) with Olivetol toProduce Δ⁹-THC Preparation of Di-p-nitrobenzoate (12)

A 25 ml three-necked roundbottom flask with a stir bar was oven-dried,fitted with septa, and cooled under N₂. (+)-p-Menth-2-ene-1,8-diol (1.00g) was added. Pyridine (6 ml, 12.6 eq.) was added and the pale yellowsolution was stirred. N,N-dimethylaminopyridine (0.1435 g, 0.2 eq.) wasadded. p-Nitrobenzoyl chloride (4.58 ml, 4.2 eq.) was added. After a fewminutes, tan solid precipitated. More pyridine (12 ml) was added. Theslurry was allowed to stir overnight at room temperature. The reactionwas quenched with water. The mixture was extracted three times withethyl acetate. The organics were combined and washed twice withsaturated NaCl (aq.), dried over Na₂SO₄, filtered and concentrated invacuo to light yellow solid. The solid was recystallized from isopropylalcohol and dried under vacuum. The yield was 3.303 g (120% yield),which clearly still contained pyridine and isopropyl alcohol by NMR. Itwas dried more and then recrystallized from ethyl acetate/hexane to givea lightly coloured solid (1.89 g, 68.7%). ¹H NMR (d₆-acetone) stillseemed to have too many aryl protons. ¹H NMR (CD₂Cl₂) δ (ppm): 8.3-8.2(m, 4H), 8.2-8.1 (m, 4H), 6.14 (dd, 1H), 5.88 (d, 1H), 3.04 (m, 1H),2.29 (m, 2H), 2.00 (m, 1H), 1.70 (s, 3H), 1.62 (s, 3H), 1.60 (s, 3H0,1.67-1.65 (m, 2H). ¹³C NMR (CD₂Cl₂) δ (ppm): 164.275, 164.244, 151.00,133.00, 131.46, 131.09, 131.04, 129.29, 124.00, 123.96, 87.04, 82.75,45.00, 34.55, 26.10. 23.83, 23.45, 22.64. m.p >200° C. (decomposition).Elemental Analysis: 59.68% C, 4.71% H, 6.07% N. R_(f) (20%EtOAc/hexane): 0.41. [α]_(D) ²⁵=+38.0° (c=0.21, CHCl₃).

One-step Reaction

A 10 ml roundbottom flask with a stir bar was oven-dried, fitted withsepta, and cooled under N₂. The di-p-nitrobenzoate (12) (116.5 mg) andolivetol (45 mg) were added. Anhydrous CH₂Cl₂ (4 ml) was added andstirred. The solution was cooled to −5° C. internal temperature.BF₃.(OEt)₂ (32 μl, 1.0 eq.) was added. The cloudy solution graduallydarkened to orange. After 2 hours, the reaction was quenched with 10%Na₂CO₃. The layers were separated and the organic layer was washed withwater and sat. NaCl, then dried over Na₂SO₄, filtered, and concentratedin vacuo to yellow oil. HPLC showed 71.5 area percent Δ⁹-THC.

1. A process for the production of a compound of general formula A:

wherein R^(c), R^(d) and R^(e) are independently H, alkyl, or substituted alkyl; and R¹ to R⁴ are independently H, OH, OR′ (R′ is alkyl, aryl, substituted alkyl or aryl, silyl, acyl, or phosphonate), alkyl, substituted alkyl, aryl, acyl, halide, amine, nitrate, sulphonate or phosphonate; comprising reacting compound B with compound C:

wherein R^(a) is H, alkyl, aryl, acyl or silyl; R^(b) is alkyl, aryl or acyl; R^(c), R^(d), R^(e) and R¹ to R⁴ are as hereinbefore defined.
 2. The process according to claim 1, wherein R^(a) is alkyl, aryl or acyl.
 3. The process according to claim 1, wherein R^(b) is an acyl group.
 4. The process according to claim 3, wherein OR^(b) is an ester group selected from the group consisting of acetate, propionate, butyrate, trimethylacetate, phenylacetate, phenoxyacetate, diphenylacetate, benzoate, p-nitrobenzoate, phthalate and succinate.
 5. The process according to claim 1, wherein both of R^(a) and R^(b) are acyl groups.
 6. The process according to claim 5, wherein OR^(a) and OR^(b) are ester groups independently selected from the group consisting of acetate, propionate, butyrate, trimethylacetate, phenylacetate, phenoxyacetate, diphenylacetate, benzoate, p-nitrobenzoate, phthalate and succinate.
 7. The process according to claim 6, wherein OR^(a) and OR^(b) are diphenylacetate.
 8. The process according to claim 1, wherein R^(c), R^(d) and R^(e) are methyl.
 9. The process according to claim 1, wherein R¹ is OR″ wherein R″ is H, alkyl, substituted alkyl, acyl or silyl.
 10. The process according to claim 9, wherein R¹ is OH.
 11. The process according to claim 1, wherein R² and R⁴ are H.
 12. The process according to claim 1, wherein R³ is C₅H₁₁.
 13. The process according to claim 1, wherein compound A is Δ⁹-THC, compound B is an ether or ester of (+)-p-menth-2-ene-1,8-diol and compound C is olivetol.
 14. The process according to claim 1, wherein the reaction of compound B with compound C is carried out in the presence of an acid catalyst.
 15. The process according to claim 14, wherein the acid catalyst is nonmetallic.
 16. The process according to claim 14, wherein 0.1-1.5 equivalents of acid catalyst are used.
 17. The process according to claim 1, further comprising performing a ring closure step.
 18. The process according to claim 8, wherein R¹ is OH, R² and R⁴ are H, and R³ is C₅H₁₁.
 19. The process according to claim 6, wherein no more than one of R^(a) and R^(b) is acetate. 